Trialkyl ammonium halides of benzhydryl-aminoethyl ether



Patented Mar. 7, 1950 TRIALKYL AMMONIUM HALIDES F BENZ- HYDRYL-AMINOETHYL ETHER and Robert W. Fleming, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation George Rieveschl, Jr.,

Grosse Pointe Woods,

of Michigan No Drawing. Application July 15, 1946, Serial No. 683,776

eciaima. (Cl. ace-561.6)

This invention relates to new quaternary ammonium halides and to methods for obtaining the same. More particularly, the invention rclates to p-(benzhydryloxy)ethyl-dimethylalkylammonium halides oi the formula,

CHO-CHaCH: I

products may be obtained by the reaction of a p-haloethyl benzhydryl ether with a dimethylalkyl-amine containing 8 to 12 carbon atoms in the alkyl radical. These processes may be carried out by heat ng the two reactants in the presence or absence of a substantially anhydrous, inert organic solvent. Such solvents are, for example, ethyl acetate, isopropanol, benzene, toluene and xylene.

The new compounds of the possess a high degree of germicidal present invention activity against pathogenic organisms and are not irritating to human skin when applied in concentrations many times greater than that necessary to kill the micro-organisms. Aqueous or alcoholic solutions of these compounds may be used for a variety of pur oses other than the app ication to cuts, wounds and abrasions. For example, they may be used in sterilizing surgical instruments, disinfecting contaminated wall or floor surfaces and as a preservative for pharmaceutical products. They may also be incorporated into soapl ke products to provide germicidal products useful in cleansing the hands, feet.- etc. These new quaternary ammonium halides are also useful as wetting agents and solubilizers.

The invention is illustrated by the following examples.

Example 1 .p- (Benzhydrylory) ethyl-dimethyl n-octylammom'um bromide aminoethyl benzhydryl ether and 22 g. of n-octyl bromide in 100 cc. of ethyl acetate is heated r under reflux.

under reflux for six hours. acetate is distilled off, the residue cooled and treated with about 200 cc. of dry ether. The product which separates as an oil solidifies on rubbing and is purified by recrystallization from isopropanol-ether mixture; M. P. 101-103 C.

The germicidal eflectiveness of this product and the other compounds of the invention may be determined by the standard Food and Drug Administration germicide test against such organisms as Eberthella typhosa, Staphylococcus aureus and Pseudomonas aeruginosa. This test is conducted by determining the dilution in water at which the germicide will kill all the organisms contained in 0.5 cc. of a twenty-four hour broth culture within five minutes at 20 C. When tested by this method p-(benzhydryloxy)ethyldimethyl-n-octylammonium bromide was found to kill Eberthella typhosa at a. dilution of 1 to 5,500, Staphylococcus aureus at a dilution of 1 to 7,000 and Pseudomonas aeruginosa at a dilution of 1 to 2000.

Example 2.--p- (Benzhydrylnmy) ethyl-dimethyln-nonylammonium bromide cm oH-o-cmornN (onmomoo Br A solution of 25 g. of n-nonyl bromide and 25.5 g. of p-dimethylaminoethyi benzhydryl ether in cc. of ethyl acetate is heated for six hours Most of the solvent is distilled from the reaction mixture, the residue cooled and treated with about 200 cc. of dry ether. The desired ,9 (benzhydryloxy) ethyl dimethyl n nonyl bromide separates as an oil but is readily crystallized on rubbing. It may be purified by recrystallization from isopropanol-ether mixture; M. P. 101.5-103.5 C.

The compound of this example when tested for germicidal activity by the test given in Example 1 kills Eberthella typhosa at a dilution of 1 to 18,000. Staphylococcus aureus at a dilution of 1 to 20,000 and Pseudomonas aeruginosa at a dilution of 1 to 2500.

Example 3.-p- (Benzhydrylory) ethyl-dimethyln-nonylammonium chloride A mixture consisting of 26 g. of p-chloroethyl an rd rl he a 1' eo ime -nonrlamine in 100 cc. of benzene isheated under reflux Most of the ethyl this example is of the same degree as thatof the corresponding bromide shown in Example 2.

Example 4.p (Benzhydrylory) ethyl-dimethyln-decylammonium bromide CHOCH|CH:

O (CHI)OCH:(7I)

25 g. 01 n-decyl bromide is added to a solution 01' 25.5 g. of p-dimethylaminoethy] benzhydryl ether in 100 cc. of ethyl acetate and the resulting solution heated on a steam bath under reflux for six hours. Most of the ethyl acetate is removed by distillation, the residue cooled and treated with about 250 cc. of dry ether. On rubbing the oily fl-(benzhydryloxy)ethyl dimethyl-n-decvlammonium bromide crystallizes to a white solid. The crude product is collected, washed with ether and purified by recrystallization from isopropanel-ether mixture; M. P. 96-8 C.

The compound of this example is particularly effective against Eberthella typhosa and Staphylococcus aureus. When tested by the test outlined in Example 1 this product was found to k ll Eberthella typhosa at a dilution of 1 to 45,000.

Staphylococcus aureus at a dilution of 1 to 40,000

and Pseudomonas aeruginosa at a dilution of 1 to 1000.

Example 5. & (Benzhydrylozy) ethyl-dimethyln-decylammonium chloride Example 6.-p (Benzhydrylozgl) ethyl-dimethuL n-hendecylammonium bromide cnocmcnm CHsho l Br 25.8 g. of n-hendec'yi bromide is added to a solution of 25.5 g. of fl-dimethylaminoethyl benzhydryl ether in 100 cc. of ethyl acetate and the resulting mixture heated on a steam bath for eight hours. Most of the solvent is distilled, the residue cooled and treated with about 250 cc. of dry ether. n stirring the oily ,B-(benzhydryloxy) ethyl dimethyl-n-hendecylammonlum bro- 4 mide crystallizes. The crude product is collected and purified by recrystallization from isopropanol-ether mixture.

The germicidal effectiveness of this product is comparable to thatoi' the corresponding compound having ten carbon atoms in the long chain alkyl group, e. g. the compound of Example 4.

Example 7.-p (Benzhydryloxy) ethyl-dimethyln-hendecylammonium iodide CH O-GKICHlN O (0 z) IICHIO') A mixture consisting of 31 g. of n-hendecyl iodide and 25.5 g. of p-dimethylaminoethyl benzhydryl ether in cc. of benzene is refluxed for eight hours, cooled and the benzene decanted. If the residue is not crystalline at this point, it is washed with ether and then stirred with a fresh portion of ether until it crystallizes. The crude fl-(benzhydryloxy)ethyl-dimethyl n hendecylammonium iodide is collected and purified by recrystallization from isopropanol-ether mixture.

The compound of this example exhibits a particularly high germicidal activity against microorganisms such as Eberthella typhosa.

Example 8.fi- (Benzhydrylozy) ethyl dimethyln-dodecylammom'um bromide /CH 0-CH2C HgN 28 g. of n-dodecyl bromide is added to a solution of 25.5 g. of fi-dimethylaminoethyl benzhydryl ether in 100 cc. of ethyl acetate and the mixture heated under reflux on a steam bath for seven hours. Most of the ethyl acetate is removed by distillation, the residue cooled and treated with 250 cc. of dry ether. The resulting oil is rubbed until it crystallizes and the crude crystalline product collected. The crude p-(benzhydryloxymthyl-dimethyl-n-dodecylammonium bromide may be purified by recrystallization from isopropanolether mixture; M. P. 97-99 C.

The d-dimethylaminoethyl benzhydryl ether and the various fl-haloethyl benzhydryl ethers used as starting materials in the practice of the present invention may be prepared as described in the copending application of George Rieveschl, Jr., Serial No. 531,639, filed April 18, 1944, now Patent No. 2,421,714, issued June 3, 1947. i

For example, the starting material used in Ex ample 1, fi-dimethylaminoethyl benzhydryl ether, may be prepared by reacting p-dimethylaminoethanol with benzhydryl bromide at -25" C. in the presence of anhydrous sodium carbonate. After the reaction has been completed, about 6 hours. water is added to the reaction mixture and the free base extracted with ether. The ether extract is extracted with 1 to 4 hydrochloric acid, the acidic extract made alkaline with 20% sodium hydroxide solution and the free base extracted with ether. After drying, the ether is distilled and the residue distilled in vacuo to obtain the free base, p-dimethylaminoethyl benzhydryl ether, boiling at -65 C./2 mm.

The other starting materials used in the practice of the invention, the p-haloethyl benzhydryl ethers, such as the compound used in Example 3, fl-chloroethyl benzhydryl ether, may be prepared as follows:

A mixture consisting of benzhydryl bromide, anhydrous potassium carbonate and ethylene 5 chlorohydrin is heated and stirred at 120130 C. for eight hours. Carbon dioxide is evolved. Benzene is added with stirring, the precipitate filtered oil and washed with benzene. The benzene is rewhere R is a straight chain alkyl radical containing 8 to 12 carbon atoms inclusive and X is a member of the class consisting of chlorine. bromine and iodine.

2. A compound of the formula, 25

6 4. A compound of the formula, cm

CHO-CHzCHzN l wmm mo) 5. A compound of formula,

6. A compound of formula,

CH-O-O HzC HzN GEORGE RIEVESCHL, JR. ROBERT W. FLEMING.

REFERENCES CITED The following references are of record in the Q file of this patent:

UNITED STATES PATENTS cE-o-cmomN o I L CH) on m Number Name Date 2,044,099 Piggott et a1. June 16, 19 6 2,087,131 Taub July 13, 1937 A the 1mm, 2,202,864 Piggott et a1. June 4, 1940 CH; 3 2,397,799 Martin et a1 Apr. 2, 1946 Q CH 2,421,714 Rieveschl June a, 194'? CHWCHCH, OTHER REFERENCES 0/ |\(CH,),CH,(,,) Winder et al., J. Pharmacol. and Exp. Ther- Br ap., vol. 87 (1946) pp. 124 and 125. 

1. A COMPOUND OF THE FORMULA, 